Substance P enhances wound closure in nitric oxide synthase knockout mice.
BACKGROUND
The neuropeptide, substance P (SP), up-regulates nitric oxide production (NO). The purpose of this study was to determine whether SP enhances response to cutaneous injury in nitric oxide synthase knockout (NOS null) mice.


METHODS
We studied mice with targeted deletions of the 3 NOS genes, neuronal NOS, inducible NOS, or endothelial NOS. Full thickness dorsal wounds were treated daily (d 0-6) with topical SP or normal saline (NaCl). Wounds were analyzed by flow cytometry for macrophage, leukocyte, endothelial, and dendritic cells. Healing time and wound epithelialization were compared using analysis of variance.


RESULTS
Wound closure in the 3 NOS null mice was slower than the control mice (P < 0.05). SP treatment enhanced wound closure in NOS null mice (P < 0.02). NOS null wounds exhibited reduced inflammation. SP increased macrophage, leukocyte, and dendritic cell densities at d 3 and d 7 (P < 0.05) in all NOS null mice. SP increased endothelial cell number in neuronal NOS and inducible NOS null mice, but not in endothelial NOS null mice (P > 0.05).


CONCLUSIONS
SP ameliorated the impaired wound healing response observed in NOS null mice by enhancing wound closure kinetics and epithelialization. SP increased inflammatory cell density in the wounds supporting the essential role of inflammatory cells, especially macrophages, in wound repair.
Muangman
Pornprom
P
Department of Surgery, University of Washington, Seattle, Washington 98104, USA.
Tamura
Richard N
RN
Muffley
Lara A
LA
Isik
F Frank
FF
Scott
Jeffrey R
JR
Xie
Chengyu
C
Kegel
Gary
G
Sullivan
Stephen R
SR
Liang
Zhi
Z
Gibran
Nicole S
NS
D000818:Animals; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D012867:Skin / Q000294:innervation / Q000378:metabolism; D017695:Soft Tissue Injuries / Q000378:metabolism; D013373:Substance P / Q000378:metabolism*; D013997:Time Factors; D014945:Wound Healing
D009569:Nitric Oxide; D013373:Substance P; D019001:Nitric Oxide Synthase